Neurofibromatosis type 1 (NF-1) is a common, inherited disease of humans, which affects the architecture and function of many tissues at a varying degree. The protein product is a large 2818 amino acid phosphoprotein, expressed almost exclusively in the brain. Learning difficulties occur in 60% of patients with mutations of NF1 (mostly truncations) and the pathogenetic mechanism is completely unknown. We have shown for the first time that (a) NF1 gene expression is induced by the secretion promoting and PKC activating histamine, (b) it associates with the plasma membrane and the underlying cortical cytoskeleton, and most importantly (c) that it is a protein kinase C (PKC) substrate. It is our hypothesis that in the normal CNS, neurofibromin is a membrane cytoskeleton-associated protein, which plays a crucial role in integrating signals mediated by membrane receptors. These signals are essential for the homeostasis of the neuronal cytoskeleton and the trafficking and release of vesicles. The presence of mutant neurofibromin leads to loss of this function and deregulates (a) neuronal circuits, causing learning disabilities and (b) neuron-glia cell interactions, leading to improper proliferation of astrocytes. This project will address the regulation of neurofibromin by phosphorylation, define NF1 for function, and determine the mechanism of NF1 protein regulation by G/PLC coupled agonists. Finally, study will be conducted on the role of human NF1-like mutations in neuronal and astrocytic function, in order to begin to address the pathogenesis of neurofibromatosis, the diversity of phenotypes in humans, and possible rescue strategies by compensating for the affected functions.